Ultrasonically enhanced substance delivery system and device

ABSTRACT

A system for enhancing delivery of at least one substance situated substantially adjacent to a surface of a subject through the surface and into the subject. The device includes at least one ultrasound emitting device secured to the subject. The at least one ultrasonic emitting device emits at least one ultrasonic signal responsively to an input alternating between a square waveform and a sawtooth waveform so as to enhance movement of at least a portion of the substance into the subject.

RELATED APPLICATIONS

This application is a continuation application and claims the priorityof application Ser. No. 09/939,507, filed Aug. 24, 2001, entitledULTRASONICALLY ENHANCED SUBSTANCE DELIVERY SYSTEM AND DEVICE, whichfurther claims priority of each of: U.S. patent application Ser. No.60/300,343, filed Jun. 22, 2001 and entitled ULTRASONIC TRANSDUCERAPPARATUS AND METHOD OF USE SUITABLE FOR ULTRASONIC DRUG DELIVERY VIA ASYSTEM WHICH IS PORTABLE AND WEARABLE BY A SUBJECT; U.S. patentapplication Ser. No. 60/300,292, filed Jun. 22, 2001 and entitledTRANSDERMAL PATCH FOR USE IN ULTRASONIC DRUG DELIVERY APPLICATIONS; and,U.S. patent application Ser. No. 60/227,359, filed Aug. 24, 2000,entitled TRANSDERMAL DRUG DELIVERY SYSTEM UTILIZING A WEARABLE, PORTABLESONIC APPLICATOR, the entire disclosures of which are each respectivelyhereby incorporated by reference herein as if being set forth in theirrespective entireties.

FIELD OF THE INVENTION

The present invention relates generally to substance delivery systems,and more particularly to portable, transdermal substance deliverysystems.

BACKGROUND OF THE INVENTION

Transdermal substance delivery systems, such as drug delivery systems,may employ a medicated device or patch affixed to an exposed surface ofa patient's skin. The patch allows a substance, such as a medicinalcompound contained within the patch, to be absorbed into the skin layersand finally into the patient's blood stream. Transdermal drug deliveryoften avoids pain associated with drug injections and intravenous drugadministration. Transdermal drug delivery may also be used to avoidgastrointestinal metabolism of administered drugs, reduce elimination ofdrugs by the liver, and for providing a sustained release of anadministrated drug. Transdermal drug delivery may also enhance patientcompliance with a drug regimen because of the relative ease ofadministration and the sustained release of the drug.

However, it is believed that several medicinal compounds are notsuitable for conventional transdermal drug delivery, since they areabsorbed through the skin with difficulty, due to the molecular size ofthe drug or other bioadhesive properties of the drug, for example. Inthese cases, when transdermal drug delivery is attempted, the drug maybe found to merely pool on the outer surface of the skin and notpermeate into the blood stream. Once such example is insulin, which hasbeen found difficult to administer by means of conventional transdermaldrug delivery.

Further, some critically needed medications are presently administeredeither by injection or oral dosage forms. In particular,chemotherapeutic agents are often administered in increased dosagesbecause of their need to survive degradation in the gastrointestinaltract, for example. Also, many critical treatments for AIDS require acocktail of drugs taken orally in solid dosage forms, several times aday, to be effective. These medications are not believed suitable forconventional transdermal drug delivery use because of the extensivedosing requirement, and the inability of the drug molecule to remainstable in a transdermal form, for example. Moreover, the unsuitabilityfor conventional transdermal to skin transfer of the drug leads to lowbioabsorbance of the drug across the skin layers.

Generally, conventional transdermal drug delivery methods have beenfound suitable only for low molecular weight medications such asnitroglycerin (for alleviating angina), nicotine (for smoking cessationregimens), and estradiol (for estrogen replacement in post-menopausalwomen). Larger molecular medications such as insulin (a polypeptide forthe treatment of diabetes), erythropoietin (used to treat severe anemia)and gamma-interferon (used to boost the immune system's cancer fightingability) are all compounds not normally effective when used withconventional transdermal drug delivery methods, for example.

Other methods of increasing the permeability of skin to drugs have beendescribed, such as iontophoresis. Iontophoresis involves the applicationof an external electric field and topical delivery of an ionized form ofdrug or unionized drug carried with the water flux associated with iontransport (electro-osmosis). While permeation enhancement withiontophoresis has been effective, control of drug delivery andirreversible skin damage are problems that may be associated with thetechnique.

Ultrasound has also been suggested to enhance permeability of the skinand synthetic membranes to drugs and other molecules. Ultrasound hasbeen generally defined as mechanical pressure waves with frequenciesabove about 20 kHz. Ultrasound signals can be generated by vibrating apiezoelectric crystal or other electromechanical element, such asthrough passing an alternating current through the material. The use ofultrasound to increase the permeability of the skin to drug moleculeshas been termed sonophoresis or phonophoresis.

However, while the use of ultrasound for drug delivery has beengenerally suggested, results have been largely disappointing in thatenhancement of permeability has been relatively low. Further, it isbelieved that there is no consensus on the efficacy of ultrasound forincreasing drug flux across the skin. While some studies report thesuccess of sonophoresis, others have obtained negative results.

Many conventional ultrasonic transdermal delivery systems envision atypical ultrasonic wand or sonicator as an ultrasonic applicator, nottaking into account the power utilization of the transducer and the sizeof the device.

Since ultrasound is rapidly attenuated in air, a coupling agent,preferably one having a low realizable absorption coefficient that isnon-staining, non-irritating, and slow drying, may be needed toefficiently transfer the ultrasonic energy from the ultrasoundtransducer into the skin. When a chemical enhancer fluid oranti-irritant, or both, are employed, they may function as the couplingagent. For example, glycerin used as an anti-irritant may also functionas a coupling agent. If needed, additional components may be added tothe enhancer fluid to increase the efficiency of ultrasonictransduction.

In general, ultrasound exposure times for permeation through human skinhave conventionally been 10 minutes to 24 hours. The depth ofpenetration of ultrasonic energy into living soft tissue is inverselyproportional to the frequency, thus high frequencies have been suggestedto improve drug penetration through the skin by concentrating the effectin the outermost skin layer, the stratum corneum.

Although it has been acknowledged that enhancing permeability of theskin may make it possible to transport molecules into the body fortherapeutic purposes, portable programmable devices and methods have notbeen disclosed.

In view of the foregoing problems and/or deficiencies, the developmentof a transducer device for safely enhancing the permeability of the skinfor noninvasive drug delivery in a more rapid time frame would be asignificant advancement in the art.

SUMMARY OF THE PRESENT INVENTION

A system for enhancing delivery of at least one substance situatedsubstantially adjacent to a surface of a subject through the surface andinto the subject, the device including: at least one ultrasound emittingdevice secured to the subject; wherein, the at least one ultrasonicemitting device emits at least one ultrasonic signal responsively to aninput alternating between a square waveform and a sawtooth waveform soas to enhance movement of at least a portion of the substance into thesubject.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more readily understood in connection withthe non-limiting, attached figures, wherein:

FIG. 1 is an artist's depiction of an ultrasonic drug deliveryapparatus, worn by a patient upon the arm.

FIG. 2 is an artist's depiction of an ultrasonic drug deliveryapparatus, worn by a patient upon the abdomen.

FIG. 3 is an illustration of the structure of human skin.

FIG. 4A illustrates a cross section view of an embodiment of thetransducer element of the present invention, said transducer elementbeing a “cymbal” type transducer design.

FIG. 4B illustrates the fabrication steps to produce a “cymbal” typetransducer element.

FIG. 4C illustrates a cross section view of transducer element a stacked“cymbal” type transducer designed to provide higher ultrasonicefficiency, intensity and power output.

FIG. 5A illustrates dimensional characteristics of an embodiment of thepresent invention, including use of a polymer potting used as aresonance compatible coupling agent coding over the surface of thetransducer element.

FIG. 5B illustrates the small dimensions obtained in the fabrication ofa “cymbal” type transducer element.

FIG. 6. illustrates an array of transducers used to enhance sonicefficiency and to provide multiple delivery sites to the skin.

FIG. 7. depicts the use of an alternating waveform suitable for drivingone or more ultrasonic transducers, which alternates from sawtooth tosquare wave.

FIG. 8A shows a scan using a HPLC of insulin, Humilin Regular, suppliedby Eli Lilly Co., where no ultrasound was applied.

FIG. 8B shows a scan using a HPLC of insulin, Humilin Regular, suppliedby Eli Lilly Co., after the sample was treated with low frequency andlow intensity ultrasound continuously over an eight hour period.

FIG. 9 shows the results of glucose analysis in the blood of subjectrats, where the transducer array was used in a test for the transdermaldelivery of insulin.

FIG. 10 illustrates a block diagram of a system according to an aspectof the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

It is to be understood that the figures and descriptions of the presentinvention have been simplified to illustrate elements that are relevantfor a clear understanding of the present invention, while eliminating,for purposes of clarity, many other elements found in conventionalultrasonic substance delivery systems. Those of ordinary skill in theart will recognize that other elements are desirable and/or required inorder to implement the present invention. However, because such elementsare well known in the art, and because they do not facilitate a betterunderstanding of the present invention, a discussion of such elements isnot provided herein.

Reference is hereby made to commonly assigned and copending U.S. patentapplication Ser. No. 09/939,435 entitled “ULTRASONICALLY ENHANCEDSUBSTANCE DELIVERY METHOD”, filed on Aug. 24, 2001, the entiredisclosure of which is hereby incorporated by reference herein.

According to an aspect of the present invention, at least one ultrasonictransducer device may be provided for enhancing transdermal substancedelivery by the use of ultrasound, especially of larger pharmaceuticallyactive compounds for example. The terms “drug” or “pharmaceuticallyactive compound” as used herein should be understood to be used in anon-limiting manner and for purposes of explanation only, as the presentinvention is suitable for delivering many substances including drugs andpharmaceutically active compounds not only transdermally, buttransmucosally as well for example. The transducer device may be smallin size, battery powered, highly efficient and able to generate anultrasonic transmission suitable for effecting the transmission of apharmaceutical compound from a transdermal patch.

The ultrasonic transducer device may be placed directly in contact witha transdermal delivery device or patch for the purpose of both enhancingand controlling the delivery of medications contained within the patchinto and through the skin layer of a target patient. The transducerdevice may be placed directly within a drug-containing patch or wornover the patch, and held in place by adhesive strips or body affixingstraps, for example. The transdermal patch may contain a particularmedication or cocktail of medications for treatment of disease or reliefof pain.

According to an aspect of the invention, the transducer device issuitable for applying ultrasound to a transdermal patch for controllingtransdermal and/or transmucosal flux rates of drugs and other moleculesinto the body and the bloodstream. A Class V flextensional cymbaltransducer and transducer array may be used to deliver low frequencyultrasound in a portable device at high efficiency for transdermal drugdelivery and therapeutic applications.

According to an aspect of the present invention, transport of drugmolecules may be accomplished using pathways associated with hairfollicles and skin pores. A method for non-invasive delivery ofbiologically active molecules through the skin and mucosal membranesusing ultrasound may be accomplished.

According to an aspect of the invention, several areas of the skin, i.e.transport sites, may be treated simultaneously or sequentially usingmultiple transducers configured into one or more transducer arrays, forexample. Various ultrasound frequencies, intensities, amplitudes and/orphase modulations may be used to control the magnitude of thetransdermal flux to achieve a therapeutic or nutritional level.According to an aspect of the invention, the programmability and fluxcontrol may allow for optimized therapeutic delivery for an individualpatient (examples may include patients that are at different stages ofthe disease, elderly patients, young, juvenile, or according to gender).The optimization may be substance specific, for example. The molecularstructure of each biologically active molecule is different and respondsdifferently to ultrasound. Control of the frequency, intensity,concentration, timing of delivery, drug regimen can optimize delivery ofeach drug type.

According to an aspect of the invention, the transducer or array oftransducers can be built into the patch or slid into the patch, forexample. According to an aspect of the invention, the transducer devicecan be used for insulin delivery.

According to an aspect of the invention, phase modulation, alternatingwaveforms and/or frequency modulation can be used to enhance ultrasonictransdermal substance transport and increase a rate of substancedelivery to a subject, e.g. human, other mammal, animal or any otherobject of which substance delivery through a surface thereof may beultrasonically enhanced. The ultrasound may be combined withiontophoresis, electroporation, depilatories, and/or chemical enhancerssuch as surfactants to facilitate transdermal permeation.

According to an aspect of the present invention, acoustical energydelivered by a portable, self-powered, programmable ultrasonictransducer placed over a substance containing patch causes the substanceto be transferred across the surface, e.g. skin, barrier.

According to an aspect of the present invention, a portable programmableultrasonic device, which may be worn by a patient over a transdermaldrug delivery patch may be provided for the purpose of enhancing thepenetration of substances such as medicinal compounds or drugs containedwithin the transdermal patch, through the skin into the patient's bloodstream. Further, the portable ultrasonic applicator may be programmed toapply acoustical energy at different times and thereby cause thedelivery of a varying quantity of the medicinal compound over time. Theportable ultrasonic applicator may be programmed to deliver a medicinalcompound to the patient continuously (sustained release) and/orintermittently (pulsed release), whichever may be deemed moreappropriate to a drug maintenance and treatment regimen for a particularpatient.

According to an aspect of the present invention a device, which may beworn by the patient, is programmed to deliver an ultrasonic signalthrough a transdermal patch according to a timing circuit. Transducersused may be sufficiently small and compact to allow for convenientportability and wearability. The transducers may be powered by abattery, which may also be portable and worn by the patient.

According to an aspect of the present invention, some parameters ofapplied ultrasound that can be changed to improve or control penetrationinclude frequency, intensity, and time of exposure. Any or all three ofthese parameters may be modulated simultaneously in a complex fashion toincrease the effect or efficiency of the ultrasound as it relates toenhancing the transdermal molecular flux rate either into or out of thehuman body.

According to an aspect of the present invention, a microprocessorcoupled with an EEPROM, a timer unit, and a waveform generator may beused to provide for programmability and time-dependent operation of thetransdermal drug delivery system. As is well understood in the pertinentarts, this is often termed a “control unit”. Of course, alternativedevices for effecting analogous controls for implementing the presentinvention may be provided. Programmability may include the ability tocontrol a quantity of drug delivered, the time interval and duration ofdrug delivery, and the frequency and intensity of the applied controlwaveforms to the transducer. Both programmable and manual operation maybe utilized. The waveform generator may be programmed to provide a sine,a square or a sawtooth waveform used to control the transducer. Ofcourse, other waveforms may also be utilized. The frequency of thecontrolled waveforms may be from about 20 kHz to about 100 kHz. Thewaveforms may be sequentially interleaved to provide different waveformsfor different durations and/or different amplitudes. Multiple waveformsmay also be generated simultaneously.

A method of superpositioning or summing of waveforms may also beprovided to combine, for example, square and sawtooth waveform at thetransducer inputs. Waveform control outputs may be applied to aplurality of transducers simultaneously or may be divided and timephased so as to permit sequential operation of different transducerelements. The timing generator and EEPROM may serve to store drugspecific delivery scenarios in memory. For example, a basal timingsequence and a bolus timing sequence may be programmed, stored, and thenretrieved and executed; thereby controlling the transducer or transducerarray in a specific drug delivery operation.

A pulsed or continuous mode of operation may also be selected. Inaddition, an electric signal, which may be directed through the skin ofthe subject at any time during the drug delivery sequence, may also beprovided. The electric signal may be programmed to be anywhere in therange of 1 to 20 Volts, for example. The electronic control unit may bebattery operated for portability and ease of use.

According to an aspect of the present invention, multiple transducersconfigured in an array may be used so as to change the area of the skinused for drug absorption, i.e. the transport sites.

According to an aspect of the present invention, transdermal delivery ofpharmaceutical agents using ultrasonic stimuli may be improved usingvariable frequencies and intensities in order to deliver therapeuticquantities of drugs to patients. Variables such as fat content and massof a particular patient's tissue, through which the drug will bedelivered, may vary the frequency and intensity requirements used toobtain an effective dosing regimen.

According to an aspect of the present invention, encapsulation ofsubstances and/or various compounds to be delivered may increase thepermeability thereof and allow for slow time release of medication, forexample. According to an aspect of the present invention, excipients maybe used to improve transport through the stratum corneum and absorptioninto the blood stream. Several substances, such as drugs, may be appliedusing this method for local application of medication.

Referring now to FIGS. 1 and 10 there is shown a wearable, non-invasive,ultrasonic-transdermal drug delivery system 10 including an ultrasonicapplicator 1 shown placed directly over a transdermal delivery device orpatch 2. The applicator 1 and/or patch 2 may be attached to an exteriorof a patient's skin 3 by means of adhesive and/or a strap 4, which holdsthe ultrasonic applicator 1 and patch 2 in place. Power for theultrasonic applicator 1 is provided by power cells 12, for example whichmay be rechargeable, and may be located within the strap 4 itself, forexample. Alternatively the power supply may be contained within theultrasonic applicator device 1 itself or provided by any conventionalexternal source.

FIG. 1 illustrates applicator 1, patch 2 and band 4 on the arm of thepatient. It should be recognized however that a system according to thepresent invention may be placed over the patient's chest (as in the caseof nitroglycerin drug delivery for example) abdomen (abdomen 6 as seenin FIG. 2), or any other suitable part of the patient's body asdetermined by the medical personnel administrating the drug treatmentregimen. Other body placements include, but are not limited to, theneck, back and legs, for example. FIG. 2 shows ultrasonic applicator 1affixed directly over the transdermal patch 2 and held onto bare skin 3of a patient, wherein the transducers 4 are placed directly in contactwith the transdermal patch 2, in this instance affixed to the patientsabdomen 3.

FIG. 3 illustrates the structure of human skin. Essentially there arethree pathways through the skin into the bloodstream: 1) breaching theStratum Corneum; 2) passing a pharmaceutical agent through pores in theskin; and, 3) passing a pharmaceutical agent through the skin byfollowing the hair follicle to the hair root, and from there into thevascular network located at the base of the hair root.

According to an aspect of the present invention, transdermal drugdelivery may be provided by utilizing drug pathways associated with thepore and the hair follicle system on the patient's skin. Moreparticularly, according to an aspect of the present invention, theultrasonic frequency, intensity level and/or waveform dynamics ofdelivered ultrasound are adjusted to exploit drug delivery through thehair follicle pathway primarily and through the pores in the skinssurface secondarily, but not directly through the stratum corneum, as itis believed the amount of energy needed for piercing the stratum corneummay be excessive and potentially damaging to fatty tissue.

According to an aspect of the present invention, through the use ofalternating waveforms, the amount of energy transmitted to the surfaceof the skin may be minimized while also providing a pressure wave effectupon the skin, enhancing drug delivery through the hair follicle andpore system. Referring to FIG. 7, according to an aspect of theinvention, an ultrasonic waveform dependent upon a sawtooth to squarewave alternation is utilized. The amplitude of and intensity of suchwave shaping aids in both the homogenization of a drug contained withinthe transdermal patch and miniaturizing a beadlet size of the activepharmaceutical substance within the patch, and in drug transport throughthe skin. The short, peaked portion of the ultrasonic waveform resultingfrom a sawtooth shaped input helps with drug homogenization, withoutimparting destructive frequencies and cavitation to the drug substance.Upon conversion to the square waveform, the ultrasonic transmission actsto massage and open the fatty tissue surrounding the hair follicle andpores. Drugs permeating from the transdermal patch are preferably inmonomer form and/or reduced in droplet size, below approximately 50Angstroms, making them more suitable in dimension to pass through theskin. The square waveform may help to “push” the drug through the poresand alongside the hair follicles, where the drug makes its way to thehair root, and directly into the bloodstream at the vascular network.

According to an aspect of the present invention, the frequency andintensity of that portion of the ultrasonic signal resulting from thesquare waveform portion and impinging a transport site may be about 20kHz at about 125 mW/sq. cm to about 225 mW/sq. cm, while the frequencyand intensity of the portion of the ultrasonic signal resulting from thesawtooth waveform portion is about 20 kHz at about 125 mW/sq. cm. toabout 225 mW/sq. cm. Further, each waveform can be provided for about100 milliseconds, before transitioning to the other, far example.

Referring again to FIG. 10, to achieve ultrasound promoted transdermaldelivery 20 of substances such as drugs, transdermal patch 2 may bedesigned to work in conjunction with ultrasonic applicator 1. Referenceis hereby made to commonly assigned and copending U.S. patentapplication Ser. No. 09/939,506, entitled “SUBSTANCE DELIVERY SYSTEM”,filed on Aug. 24, 2001, the entire disclosure of which is herebyincorporated by reference herein. In summary, this application describesa patch suitable for use in combination with the present invention, andthe reader is advised to study this application for a more detailedanalysis there-regarding. In particular, the contact between theapplicator and the patch preferably promotes efficient acoustic energytransmission. The selection of the materials and adhesives is importantto maintain the intensity and power output of the ultrasonictransmission from the transducers through the transdermal patch. It isbelieved that insulin, one of many active pharmaceutical substancesbeing suitable for enhanced drug delivery via the present invention, hasa large molecule size, and forms hexamers generally over about 50Angstroms, making it difficult to permeate through the pores of theskin. Further, insulin molecules tend to agglomerate when stored.Insulin stored within the patch may therefore tend to agglomerate intoeven larger drug clump sizes, further reducing skin transport potential.

To help alleviate this problem and to keep the drug at a sizesufficiently small enough for skin transport, the ultrasonic signal maybe altered, from time to time, using a sawtooth to a square waveformstimuli. It should be understood, however, that other varying waveformshaving alternating average imparted powers, for example, can of coursebe utilized. Nonetheless, for purposes of illustration FIG. 7 shows analternating waveform, wherein a sawtooth waveform (of relatively lowaverage power) is used to drive one or more transducers to homogenize adrug within a patch, leading to increased skin transport as theultrasonic waveform stimuli switches to a square wave shape (ofrelatively high average power). As will be readily understood by thosepossessing an ordinary level of skill in the pertinent arts, thesawtooth waveform portion leads to a short period of high energy, with ashort duration of pressure amplitude, leading to a vibration effect withthe targeted pharmaceutical substance. This vibration is with a low heatpotential and may have the effect of mixing or homogenizing the drugwithin the patch. Thus, smaller beadlet sizes may be made possible bythe sawtooth waveform portion.

Conventional transdermal substance delivery pathways through the stratumcorneum may enable initial quantities of a drug to permeate through theskin, but as longer periods of ultrasound are applied to the samelocation on the skin the delivery rate may drop off or be reduced tozero. This may imply that ultrasound applied to same site at the skin'ssurface should not be continued for lengthy periods of time. It isbelieved that one or more attempts in the previous art to breach thestratum corneum failed over time because cavitation eventuallyover-heated the fatty tissue contained within the epidermis, resultingin a changed density of the fatty composites within this skin layer. Anincrease in such density may retard further drug permeation through theskin.

FIG. 4A illustrates the design of a cymbal type of ultrasonic transducer40 which can be utilized according to an aspect of the presentinvention. Cymbal transducer 40 includes piezoelectric disc 41, such asPZT4 available from Piezokinetics Corp., Bellefonte, Pa., connected totwo metal caps 42, which may be composed of titanium foil for example.FIG. 4A illustrates that there is a hollow air space 43 between thepiezoelectric disc 41 and the end caps 42. The end caps 42 are connectedto the piezoelectric disc 41 by a non-electrically conductive adhesive44 to form a bonded layered construction to the transducer 40. Cymbaltransducers offer a thin, compact structure well suited for a portableultrasonic drug delivery apparatus. Additionally such a transduceroffers sufficient efficiency for the conversion of electric power toacoustically radiated power. Such a transducer design also providespotential to be battery powered, and is small and lightweight.

FIG. 4C illustrates a stacked cymbal type of ultrasonic transducer 40which can be utilized according to an aspect of the present invention.In a stacked transducer construction greater intensity of ultrasonicsignals can be utilized. U.S. Pat. No. 5,729,077, issued Mar. 17, 1998,entitled “METAL-ELECTROACTIVE CERAMIC COMPOSITE TRANSDUCER” (Newnham etal.), the entire disclosure of which is incorporated by referenceherein, discloses the use of stacked transducers, essentiallytransducers fitted atop each other, to increase ultrasonic intensitieswhile maintaining a given frequency level. A stacked transducerconstruction may be used to increase intensity while improving the powerutilization of the transducer system.

FIG. 5A illustrates the sizing of the transducers which may be used, andwhich can be about 0.5″ inches in diameter. The use of such a relativelysmall size transducer enables the transducers to fit within thedimensions of a transdermal patch, for example. In addition the smallsize enables a lower weight potential for the transducers, again aidingin the portability of the invention. The transducer element 50 is acymbal type construction attached to a power cable 51. The transducerelement 50 is coated in a polymer housing 52, composed of a polyurethanematerial suitable for castings, coatings, and/or adhesives, such as aUralite resin for example, which is used to avoid short circuits betweenthe two metallic caps 42 (See, FIG. 4A) and provides acoustic couplingfor the sonic transmission.

FIG. 5B illustrates possible dimensions using a “cymbal” type transducerelement. The cymbal type transducer design offers several advantages tothe present invention, including, but not limited to: compact structure,with small surface area; high acoustic pressure and high acousticintensity at low resonance frequency; high efficiency, making the systemrequire less driving power; the use of low resonance frequency to avoida high cavitation threshold, i.e., the intensity required to generateair bubbles within the stratum corneum of the patient's skin tissue. Thecavitation threshold is inversely proportional to the frequency appliedso the choice of a low resonance frequency of the transducer permits alower acoustical pressure applied to the surface of the skin andtransdermal drug delivery is effected.

For a more thorough discussion regarding cymbal transducers in general,the reader is referred to the following U.S. Pat. Nos. 4,999,819, issuedMar. 12, 1991, entitled “TRANSFORMED STRESS DIRECTION ACOUSTICTRANSDUCER” (Newnham, et al), 5,276,657, issued Jan. 4, 1994, entitled“METAL-ELECTROACTIVE CERAMIC COMPOSITE ACTUATORS” (Newnham, et al) andthe aforementioned 5,729,077 (Newnham, et al), the entire disclosures ofwhich are hereby respectively incorporated by reference as if being setforth in their respective entireties herein.

FIG. 6 shows an array 60 including more than one-cymbal element 61arranged in a pattern (or array) onto a substructure or encased within apolymer housing 62. The array can take any suitable form, such as a 2×2array or a 3×3 array, for example. The cymbal elements 61 may beconnected in parallel by a series of electrical connections 63. Thearray 60 may be sealed in polymer potting material 62, again composed ofUralite for example. Such an array enables a portable, battery powered,ultrasonic transmission with sufficient power to effect drug deliveryvia a transdermal patch.

According to an aspect of the present invention, the sonic applicator 1,as shown in FIG. 6, can transmit ultrasonic signals through multipletransducers, that is at multiple transport sites. The activation of oneor more elements of the transducer array may be sequenced fromtransducer element to transducer element, optionally using differentwaveforms, frequency, amplitudes, and duty cycles between eachtransducer element, for example. It is believed that this serves toadvantageously relieve the skin transport sites from continualultrasonic stress and provide increased variability in ultrasonic skintransport energy manipulation. The transducers can act in tandem,transmitting together.

The transducer array as shown in FIG. 6 provides for spreading out drugpathway sites along the skin surface by providing ultrasonictransmission from the multiple transducer elements 61 of the arrayacting upon the skin. The transducer elements 61 may be activatedsimultaneously or sequentially to transmit ultrasound through a patchand through differing multiple sites on the skin surface, for example.Additionally, the frequency, intensity and/or waveform of an appliedsignal may be altered at each transducer element 61 within the array 60.This variation may result in increased efficiency, enhanced powerutilization and lengthening the life span of the battery of the portablesystem, for example. Additionally, alternating transducer elements 61may help keep a drug homogenized within a pocket of the transdermalpatch and help ensure that the skin is not overexposed to an excessivefrequency of ultrasound.

An array of two or more transducers, of the cymbal type for example, mayhelp to push drugs through multiple skin transport sites. The transducerarray may further reduce skin damage and improve an efficiency andtransmitted acoustical intensity. By alternating the transduceractivation sequence for example, it is possible to mitigate skinexertion and to assure greater longevity for the skin transport sites.

The application of ultrasound according to the present invention can becoupled with iontophoresis, the application of electric currents appliedto the skin, in various forms of substance, or drug, delivery.Ultrasound can be applied together with iontophoresis or as apre-treatment to the application of iontophoresis, for example.Iontophoresis and/or electroporation in combination with the method andapparatus of the present invention may be used to enhance moleculartransport through the skin. According to an aspect of the presentinvention, chemical substances, such as chemical enhancers, may be usedto enhance substance transport as well.

The present invention may be used to enhance delivery of a wide varietyof substances, such as medications or medicaments, nutritionalsupplements or any other suitable substance to a subject, such as ahuman patient. As described in greater detail herein below, a medicationfor example may be delivered transdermally, transcutaneously,intralumenally, and within solid tissue sites, where in all casesabsorption of the medication or a pharmacologically active portionthereof into the underlying or surrounding tissue is phonophoreticallyenhanced by the application of ultrasonic or sonic energy. Thesubstance, or medicament for example, may take any conventional form,including liquids, gels, porous reservoirs, inserts, or the like, andthe medication or pharmacologically active portion thereof may beintended to treat or alleviate an existing condition or prophylacticallyprevent or inhibit another condition of the patient. The effect of themedication may be local, such as providing for anti-tumor treatment, ormay be systemic. Suitable medicaments include broad classes of compoundsnormally delivered through the skin and other body surfaces or intosolid tissues, for example.

In general, such medications may include or incorporate anti-invectivessuch as antibiotics and antiviral agents; analgesics and analgesiccombinations; anorexics; antihelminthics; antiarthritics; antiasthmaticagents; anticonvulsants; antidepressants; antidiabetic agents;antidiarrheals; antihistamines; anti-inflammatory agents; antimigrainepreparations; antinauseants; antineoplastics; antiparkinsonism drugs;antipruritics; antipsychotics; antipyretics; antispasmodics;anticholinergics; sympathomimatics; xanthine derivatives; cardiovascularpreparations including potassium and calcium channel blockers,beta-blockers, and antiarrhythmics; antihypertensives; diuretics;vasodilators including general coronary, peripheral and cerebral;central nervous system stimulants; cough and cold preparations,including decongestants; hormones such as estradiol and other steroids,including corticosteroids; hypnotics; immunosuppressives; musclerelaxants; parasympatholytics; psychostimulants; sedatives; andtranquilizers. By the method of the present invention, both ionized andnonionized drugs may be delivered, as can drugs of either high or lowmolecular weight.

Proteinaceous and polypeptide drugs represent a class of drugs beingsuitable for use in conjunction with the presently disclosed invention.As will be evident to those possessing an ordinary skill in thepertinent arts, such drugs cannot generally be administered orally inthat they are often destroyed in the gastrointestinal tract ormetabolized in the liver, for example. Further, due to the molecularweight of most polypeptide drugs, conventional transdermal deliverysystems are not generally effective.

Common examples of pharmaceutical or nutritional compounds which may beused with the present invention, and may be contained within atransdermal patch for example, include, but are not limited to:Acetaminophen, Antibiotics, Aspirin, Corticosterone, Erythromycin,Estradiol, Ibuprofen, Insulin, Nitroglycerin, Nicotine, Steroids such asProgesterones, Estrogens, Vitamins.

Other substances, such as pharmaceutical or nutritional compounds, fornutraceutical, medicinal or pharmaceutical use may also be utilized. Itmay also be desirable to use the method and apparatus of the inventionin conjunction with substances, such as drugs, to which the permeabilityof the skin is relatively low, or which may give rise to a longlag-time. Application of ultrasound as described herein is believed tosignificantly reduce the lag-time involved with the transdermaladministration of most drugs.

Applicants have noted that many drugs may be immersed within anexcipient binder fluid, such as saline or an acetate composition, tomake them injectable. Insulin is often placed in acetate mixes forexample. By altering the excipient solution transdermal transport andthe homogenization effect within a patch pocket may be hastened andenhanced in conjunction with the application of ultrasound. Excipientsolutions high in metallic or salt content, for example, may enhance theinteraction between the drug and ultrasound. It is believed that theeffect of ultrasound at high intensity, or at low intensity butgenerating cavitation, can have a damaging effect upon many drugsubstances, such as insulin, whereupon a protein may become altered ordamaged by excessive ultrasonic or cavitation frequencies andintensities. Using an appropriate excipient carrier solution, selectedconsistently with conventional techniques for example, a substance, suchas an active drug, may mitigate damage to the substance such that itremains biofunctional after skin transport.

The following non-limiting examples are provided for purposes ofproviding a clear understanding of particular embodiments of the presentinvention.

According to an aspect of the present invention, the Cymbal Transducerscan be constructed as follows: the piezoelectric ceramic material cantake the form of a PZT4 disc 0.5-inch diameter, 1-mm thickness (PK1402)SD 0.500-0.000-0.040-402. This is available from Piezo Kinetics Inc.,Mill Road and Pine St., PO Box 756, Bellefonte, Pa. 16823, for example.Titanium caps can be formed of Alfa Aesar, Titanium Foil, 0.25 mm thick,metal basis 5%, Item #10385, available from Alfa Aesar, A JohnsonMatthey Company, 30 Bond Street, Ward Hill, Mass. 01835-8099, USA. Abonding layer material can take the form of Eccobond 45LV+catalyst 15LV,available from Emerson & Cuming, 46 Manning Road, Billerica, Mass.01821. Low temperature soldering material suitable for use in connectionwith the Cymbal transducers include Indalloy Solder #1E, 0.30″diameter×3 ft. long, which is available from The Indium Corporation ofAmerica, 1676 Lincoln Ave., Utica, N.Y. 13502. Wires can be formed fromstranded wire, Gauge/AWG: 30, Catalog number (Digikey): A3047B-100-ND,Note: Maximum Temperature: 80 C., Conductor Strand: 7/38, Voltage Range:300V, Number of Conductors: 1, available from Alpha Wire Corporation. Apolymer housing can be formed of Uralite FH 3550 part A/B, availablefrom the HB Fuller Company. Ethyl Alcohol used is preferably about 200proof, and fine scale sand paper can be utilized.

Referring to FIG. 4B, the titanium foil may be dye cut titanium foilsinto several disks using a circular saw having 10.7 min diameter, forexample. One side of the disks results with edges as is conventionallyunderstood, these edges may be removed with sand paper (fine scale). Analcohol bath can then be used to remove dust generated by sanding thedisks. The disks may then be placed into a high pressure (12000 torr)shaping tool (polished side up). This step may be performed using acustom-made punch dye in order to shape the disks into the dimensionsreported in FIG. 2, for example. Resulting rough edges can again besanded, and the sanded disk again immersed in alcohol to remove dust.The disk may be wiped to remove alcohol and dust from disk.

The thickness of the cap may be measured using conventional techniques.Caps having matching or substantially matching thicknesses may bematched together. This step may be accurate, because slight differencesbetween the two caps may generate spurious resonance into the cymbal.

The piezo disk ceramic (piezo disks) may be cleaned with alcohol. Epoxybond may then be screen printed onto both sides of the piezo diskceramic using a process similar to T-shirt screen-printing for example.A ring of epoxy may be generated to glue the caps with the disks. Thisring may be accurate and regular in order to avoid spurious resonances.

The cymbals may then be placed on ceramic disks, and the compositestructure placed into a press. This press may just keep the cymbal madein place, a tool where several cymbals are kept in place, for example.The pressed, compound structures may then be heated to approximately 70°C. for four (4) hours utilizing an oven, for example. The wires may thenbe soldered (45) using a maximum temperature of about 270° C. at theelectrical contact points, 4 points per piece, for example.

A transducer produced by the above procedure may be termed to be of astandard construction. To form a stacked construction transducer, two ormore transducers 40 may be placed directly atop one another as shown inFIG. 4C and fitted together. To form an array, the transducers may begenerally connected in parallel, electrically within the polymer orepoxy bonding material as shown in FIG. 6, in either single element formor in a stacked construction format, for example.

A series of physical tests were conducted using the single elementcymbal transducer fabricated according to the steps outlined above,using standard analysis procedures common to the ultrasonic andtransducer industry. The single element transducer is a highly efficientsystem producing an ultrasonic transmission within two ranges: RANGE - ATRANSDUCER TYPE Single element “Cymbal” design FREQUENCY 20 kHzINTENSITY: LOWEST SETTING 125 mW/sq. cm. DESIGN Standard ConstructionRANGE - B TRANSDUCER TYPE Single element “Cymbal” design FREQUENCY 20kHz INTENSITY: LOWEST SETTING 225 mW/sq. cm. DESIGN Stacked Construction

Referring again to FIG. 6, a series of physical tests were conductedusing an array of cymbal transducer elements fabricated according to thesteps outlined above, using standard analysis procedures common to theultrasonic and transducer industry. The single element transducer is ahighly efficient system producing ultrasonic transmission within tworanges: RANGE - A TRANSDUCER TYPE Single element “Cymbal” designFREQUENCY 20 kHz INTENSITY: LOWEST SETTING 125 mW/sq. cm. DESIGNStandard Construction using nine elements RANGE - B TRANSDUCER TYPESingle element “Cymbal” design FREQUENCY 20 kHz INTENSITY: LOWESTSETTING 225 mW/sq. cm. DESIGN Stacked Construction using nine elements

Arrays with different orientation of cymbals and with combinations ofstandard and stacked arrays may be used to increase efficiencies and toimprove the effective delivery of drugs.

Alternating frequency outputs from the transducer array may be obtained.In tests, an array using nine-single elements in a standard constructionand in a stacked construction produced frequency outputs, which could bevaried from about 20 kHz to about 100 kHz. Ultrasonic transmissions werefound to be most uniform at the lower frequency range, i.e. about 25 kHzas compared to 40, 60 or 80 kHz. Ultrasonic transmissions were foundirregular at these higher frequencies. In all cases, the transducerscould be made to emit responsively to a purely sinusoidal waveform or beconverted to a combination waveform including sawtooth and square wavesas illustrated in FIG. 7. In these tests the ultrasonic driver circuit,e.g., the frequency generator, was set to propagate 100 milliseconds ofsawtooth waveform followed immediately by 100 milliseconds of squarewaveform, before re-cycling back to sawtooth waveform.

The transducers, whether configured in a single element or as an array,in either a standard or stacked construction, operate using low power.The portable nature of the final drug delivery device, as depicted inFIGS. 1 and 2 for example, is achieved by the present system, which isworn by the patient. Accordingly, a portable power source, such as arechargeable battery, can be used to drive the ultrasonic system. As aresult, according to an aspect of the invention: 1) low power is used todrive the transducer, from standard commercially available batterysources for example; and, 2) long duration power, providing at least onefull day of continuous power is provided.

Tests were conducted using a nine element standard cymbal design arrayset to operate at 20 kHz frequency and at varying intensity levels,powered by a standard “A” or “C” type battery. A useful power life of 25hours was obtained at an intensity level of 200 mW/sq. cm., withcontinued constant usage to the transducer array. Of course, othersuitable power sources can be used, such as “9 Volt” type batteries, forexample.

Thus, transducers used may be effectively battery powered so as to drivethe ultrasonic signal, and have an efficiency of the power utilizationsuch that a low battery drain rate is exhibited, thereby extending thelife of the power source. Accordingly a portable or wearable ultrasonicdrug delivery system employing ultrasonic drug delivery is possibleutilizing conventional battery sources coupled with the transducerswhich may be used according to the present invention.

The effect of the ultrasonic signal discussed in connection with thepresent invention upon an active pharmaceutical substance was tested.High intensity and high frequency ultrasound may be capable of inducinga cavitation effect with a drug, leading to an increase in temperatureand a degradation of the drug molecule. Insulin (HumulinRegular-supplied by the Eli Lilly Company) was subjected to ultrasoundemitted from a stacked array of the transducers as described above, setto operate at 20 kHz frequency and at 125 mW/sq. cm intensity level, forone, eight and eleven continuous hours of exposure. The insulin wasplaced in a plastic pouch within a hydrophone tank containing water andstirred during ultrasonic exposure. A control sample, which wasuntreated, but allowed to sit in the pouch and tank for one, eight andeleven hours, was also made. Samples were sent for independent analysis.All samples showed no change in the insulin from the untreated insulin.

FIG. 8A shows the HPLC scan of the control sample, showing nodegradation of either the insulin or the excipient solution of theHumulin Regular sample. FIG. 8B shows the HPLC scan of theultrasonically treated eight hour sample, showing that there also was nodegradation of either the insulin or the excipient solution of theultrasonically treated Humulin Regular sample, even after eight hours ofcontinuous exposure.

Accordingly, there appears to be no damage caused to the insulinmolecule as a result of exposure to ultrasonic transmissions associatedwith the present invention (e.g. low frequency, low intensity andalternating waveform, for example).

A four-element transducer was fabricated using four standard cymbalelement transducers in one array system (Array # 1) and four stackedcymbal element transducers in another system (Array # 2). Array # 1, thestandard array, was set to operate at 20 kHz frequency and at 125 mW/sq.cm intensity level. Array # 2, the stacked array, was set to operate at20 kHz frequency and at 225 mW/sq. cm intensity level.

The transducer arrays were fitted with a reservoir at a bottom end, intowhich Humulin Regular Insulin (supplied by Eli Lilly Company) wasinserted. A total of 100 cc of insulin was added, providing 100 units ofinsulin for each test.

Ten test rats were assembled and anesthetized. The belly of the ratswere shaved to produce a skin area as close in configuration as would bepresent in a human situation. The transducer arrays were placed directlyonto the rat skin surface and adhered to the skin by means of adhesive.Two groups of test rates were assembled. The first group (Group-1) weresubjected to ultrasonic transmission while the second group (Group-2)received no ultrasound. In the second group (Group-2), the transducerarrays were loaded with insulin and the insulin was allowed to pool ontothe surface of the rat skin, but there was no active ultrasonictransmission.

Next a frequency generator was employed to propagate a pulsed ultrasonictransmission, which used 100 millisecond pulses, with a pulse rate ofone pulse per second, and a duty cycle of 10%, for one hour.

Both Group-1 and Group-2 animals were tested for 120 minutes. Bloodsamples were taken from the animals according to standard investigativeprocedure every 30 minutes for the first hour and every hour after andanalyzed for glucose levels and the presence of insulin. The Group-1animals were exposed to ultrasound for 60 minutes, after which theultrasound was terminated for the balance of the test period. Glucoselevels in both groups were observed over the 120 minute period.

FIG. 9 illustrates the results of these tests, with an average of thedata compiled across the number of tests conducted. Specifically thisdata relates the average Glucose level of the Group-1 animals treatedwith ultrasound and the Group-2 animals, which were untreated, but wherethe insulin was placed in a blank array (containing no transducers) andplaced upon the skin surface. At minute 0, before the ultrasound wasactivated, both groups had similar starting glucose levels. At minute 30and minute 60 the Group-1 animals showed a significant reduction inglucose levels while the Group-2 animals showed no lowering in glucoselevel. At minute 60, the ultrasound was terminated and the animalsmonitored for another 60 minute period. The Group-2 animals showed nodecrease in glucose levels, as the insulin was not absorbed through theskin. The Group-1 animals, which had a lowering of their glucose levelsduring active ultrasound transmission, indicating that the ultrasoundenabled the permeation of the insulin through the skin, were observed tohave a rise in their glucose levels upon termination of the ultrasound.

At minute-120 the Group-2 animals showed no decrease while the Group-1animals showed their glucose levels to be rising to the previouspre-ultrasound levels. This test showed that the insulin was onlypermeated through the skin via the ultrasound emitted from thetransducer arrays, and only with the presence of active ultrasound. Thetests also confirmed that insulin, placed on the skin or delivered via atransdermal patch did not permeate through the skin on its own. Thesetests also confirm the validity of the transducer designs describedherein as an effective means for delivering ultrasonically enhancedtransdermal drug delivery.

These tests also showed that insulin delivered transdermally by theportable transducers can effectively decrease glucose levels. Thisresult showed that the insulin is not only absorbed through the stratumcorneum but it is also absorbed into the bloodstream in an effectiveform and can cause its metabolic effect of lowering glucose.

Examination of the skin features of the tested rats showed no damage tothe skin surface, no discoloration or abnormal fractures after theapplication of ultrasound emitted from the transducers.

The device of this invention provides certain drug delivery functions,including but not limited to: non-invasive drug delivery through the useof ultrasound applied transdermally to a patient's skin surface;penetration/absorption enhancement through the skin so that medicinescontained within a transdermal patch become more readily absorbedthrough the skin layers into a patient's blood stream; homogenizationand droplet size reduction of pharmaceutical agents contained within atransdermal patch, to make the resulting ultrasonically treated drugmore readily absorbable through a patient's skin layers. The method andapparatus of the present invention may be especially well suited fordifficult to administer drugs such as insulin and various hormonemedicines; the device may go with the patient, to be wearable by thepatient, and use rechargeable batteries to provide treatment mobility.

Some elements of this invention also worthy of noting include, but arenot limited to: (a) The ability to provide a portable and wearableultrasonic drug delivery device which goes with the patient. (b) The useof drug delivery pathway which includes hair follicle and skin poredelivery as opposed to breaching the stratum corneum. The drug containedwithin the drug pocket of the transdermal patch may ultimately penetrateinto the patient's blood stream, aided by the sonic transmission throughthe skin pores or hair follicles and into the muscular of the patient.This pathway approach may reduce the chance of damaging the skin andenables the use of lower ultrasonic frequencies and intensities. (c) Theuse of a transducer array, which enables ultrasonic skin transport atmore than one site on the skin, which may provide a greater chance ofeffective skin transport and avoid overtaxing just one delivery site.The use of multiple transducers may offer varied treatment effects tofacilitate maximum skin transport of the target active pharmaceuticalagent, by providing tandem drug transport across multiple transducerelements, by enabling sequencing of the transducer elements in thearray, whereupon the transducers may act at different frequencies andintensity levels of ultrasound. (d) Using an array of transducers in aportable, wearable ultrasonic drug delivery device, especially utilizingcymbal type transducers, may provide higher power utilizationefficiencies and helps to avoid the damaging effects of excessivecavitation upon the skin. Using an array may help enable long durationbattery supplies providing sufficient power to enable the apparatus tofunction for several days between recharge or replacement cycles. Theuse of a rechargeable battery supply, with batteries contained with thestrap of the device for example, may afford total mobility for thepatient and a reliable power supply for the device over several monthsof recycled use, for example. (e) Applicants further note that the useof transmission in both the sonic and ultrasonic ranges may be combinedto achieve optimal transport through the skin or mucosal membranes. (f)To deliver the proper dose of a drug across the skin, in minutes asopposed to the hours noted in the previous art. (g) The use of lowfrequency ultrasound, from about 20 kHz-about 100 kHz, with analternating waveform (from sawtooth to square wave for example), withcymbal type transducers, may enable battery powered ultrasonictransmission. Further, a transducer array may help to avoid overexerting a single skin transport site and providing versatility inultrasonic frequency and intensity ranges per transducer element.

Having described the invention in the above detail, those skilled in theart will recognize that there are a number of variations to the designand functionality for the device, but such variations of the design andfunctionality are intended to fall within the present disclosure.Further, although the invention has been disclosed with a certain degreeof particularity, it is understood that the present disclosure of thepreferred forms has been made by way of example, and that numerouschanges in the details of construction and combination and arrangementof parts and steps may be made without departing from the spirit andscope of the invention as hereinafter claimed.

1. A device for enhancing delivery of at least one substance situatedsubstantially adjacent to a surface of a subject through said surfaceand into said subject, said device comprising: at least one ultrasoundemitting device secured to said subject; wherein, said at least oneultrasound emitting device emits at least one ultrasonic signaldependent upon a waveform alternating input to enhance movement of atleast a portion of said at least one substance into said subject.
 2. Asystem for enhancing delivery of at least one substance situatedsubstantially adjacent to a surface of a subject through said surfaceand into said subject, said system comprising: at least one ultrasoundemitting device secured to said subject; wherein, said at least oneultrasound emitting device emits at least one ultrasonic signalresponsively to an input alternating between a square waveform and asawtooth waveform to enhance movement of at least a portion of said atleast one substance into said subject.
 3. The device of claim 1, whereinsaid waveform alternating input comprises at least a square waveformportion.
 4. The device of claim 3, wherein said waveform alternatinginput comprises at least a saw tooth waveform portion.
 5. The device ofclaim 1, wherein said device is wearable to said subject.
 6. The deviceof claim 1, wherein said device is programmable.
 7. The device of claim1, wherein said at least one ultrasonic signal has a frequency greaterthan about 20 kHz.
 8. The device of claim 1, wherein said at least oneultrasonic signal has a frequency less than about 100 kHz.
 9. The deviceof claim 1, wherein said delivery of said at least one substance is viaa combination of hair follicles and a pore system of said surface ofsaid subject.
 10. The device of claim 1, wherein said at least oneultrasound emitting device comprises at least one cymbal typetransducer.
 11. The device of claim 1, wherein said at least onesubstance is insulin.
 12. The device of claim 1, further comprisingmeans for securing said device to said subject.
 13. The system of claim2, wherein said system is wearable to said subject.
 14. The system ofclaim 2, wherein said system is programmable.
 15. The system of claim 2,wherein said at least one ultrasonic signal has a frequency greater thanabout 20 kHz.
 16. The system of claim 2, wherein said at least oneultrasonic signal has a frequency less than about 100 kHz.
 17. Thesystem of claim 2, wherein said delivery of said at least one substanceis via a combination of hair follicles and a pore system of said surfaceof said subject.
 18. The system of claim 2, wherein said at least oneultrasound emitting device comprises at least one cymbal typetransducer.
 19. The system of claim 2, wherein said at least onesubstance is insulin.
 20. The system of claim 2, further comprisingmeans for securing said device to said subject.